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Inhibition of Cdk5 increases osteoblast differentiation and bone mass and improves fracture healing

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Bone Research 2022年第3期10卷 469-481页

作者： Mubashir Ahmad benjamin Thilo krüger Torsten kroll Sabine Vettorazzi Ann-kristin Dorn Florian Mengele Sooyeon Lee Sayantan Nandi Dilay Yilmaz Miriam Stolz Naveen Kumar Tangudu David Carro Vázquez Johanna Pachmayr Ion Cristian Cirstea Maja Vujic Spasic Aspasia Ploubidou Anita Ignatius Jan Tuckermann Institute of Comparative Molecular Endocrinology(CME) Ulm UniversityHelmholtzstrasse 8/189081 UlmGermany Institute of Orthopedic Research and Biomechanics Ulm UniversityHelmholtzstrasse 1489081 UlmGermany Leibniz Institute on Aging–Fritz Lipmann Institute(FLI) Beutenbergstrasse 11D-07745 JenaGermany Praxisklinik für Orthopädie Unfall-und Neurochirurgie Prof.Bischoff/Dr.Spies/Dr.Mengele89231 Neu-UlmGermany Paracelsus Medizinische Privatuniverstät Institute of PharmacyStrubergasse 215020 SalzburgAustria Department of Endocrinology Ludwig Maximilians University MunichMunich 80336Germany Present address:Institute of Orthopedic Research and Biomechanics Ulm UniversityHelmholtzstrasse 1489081 UlmGermany Present address:UPMC Hillman Cancer Center Department of Pharmacology and Chemical BiologyUniversity of Pittsburgh5115 Center Avenue15232 PittsburghPAUSA Present address:TAmiRNA GmbH Leberstrasse 201110 ViennaAustria

Identification of regulators of osteoblastogenesis that can be pharmacologically targeted is a major goal in combating osteoporosis,a common disease of the elderly population. Here, unbiased kinome RNAi screening in primary murine osteoblasts identified cyclin-dependent kinase 5(Cdk5) as a suppressor of osteoblast differentiation in both murine and human preosteoblastic cells. Cdk5 knockdown by si RNA, genetic deletion using the Cre-lox P system, or inhibition with the small molecule roscovitine enhanced osteoblastogenesis in vitro. Roscovitine treatment significantly enhanced bone mass by increasing osteoblastogenesis and improved fracture healing in mice. Mechanistically, downregulation of Cdk5 expression increased Erk phosphorylation, resulting in enhanced osteoblast-specific gene expression. Notably, simultaneous Cdk5 and Erk depletion abrogated the osteoblastogenesis conferred by Cdk5 depletion alone, suggesting that Cdk5 regulates osteoblast differentiation through MAPK pathway modulation. We conclude that Cdk5 is a potential therapeutic target to treat osteoporosis and improve fracture healing.

关键词： Cdk5 healing expression

Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets

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Neural Regeneration Research 2025年第3期20卷 725-739页

作者： benjamin R.Helmold Angela Ahrens Zachary Fitzgerald P.Hande Ozdinler Department of Neurology Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Center for Molecular Innovation and Drug Discovery Center for Developmental TherapeuticsChemistry of Life Processes InstituteNorthwestern UniversityEvanstonILUSA Mesulam Center for Cognitive Neurology and Alzheimer’s Disease Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Feinberg School of Medicine Les Turner ALS Center at Northwestern UniversityChicagoILUSA

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.

关键词： ALS2 alsin amyotrophic lateral sclerosis hereditary spastic paraplegia neurodegenerative diseases personalized medicine precision medicine protein interactome protein-protein interactions SPAST spastin

Numerical investigation of the dynamics of a rigidspherical particle in a vortical cross-slot flow atmoderate inertia

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Microsystems & Nanoengineering 2023年第4期9卷 181-195页

作者： Konstantinos Kechagidis benjamin Owen Lionel Guillou Henry Tse Dino Di Carlo Timm krüger School of Engineering Institute for Multiscale ThermofluidsUniversity of EdinburghW Mains RdEdinburgh EH93JW ScotlandUK Cytovale Inc.Executive Park Blvd.San Fransisco CA 90095 CAUSA Department of Bioengineering University of CaliforniaWestwood PlazaLos Angeles 610101 CAUSA

The study of flow and particle dynamics in microfluidic cross-slot channels is of high relevance for lab-on-a-chipapplications. In this work, we investigate the dynamics of a rigid spherical particle in a cross-slot junction for a channelheight-to-width ratio of 0.6 and at a Reynolds number of 120 for which a steady vortex exists in the junction *** an in-house immersed-boundary-lattice-Boltzmann code, we analyse the effect of the entry position of theparticle in the junction and the particle size on the dynamics and trajectory shape of the particle. We find that thedynamics of the particle depend strongly on its lateral entry position in the junction and weakly on its vertical entryposition;particles that enter close to the centre show trajectory oscillations. Larger particles have longer residencetimes in the junction and tend to oscillate less due to their confinement. Our work contributes to the understanding ofparticle dynamics in intersecting flows and enables the design of optimised geometries for cytometry and particlemanipulation.

关键词： particle dynamics spherical

Can DyeCycling break the photobleaching limit in single-molecule FRET?

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Nano Research 2022年第11期15卷 9818-9830页

作者： benjamin Vermeer Sonja Schmid NanoDynamicsLab Laboratory of BiophysicsWageningen UniversityStippeneng 46708WE WageningenThe Netherlands

Biomolecular systems,such as proteins,crucially rely on dynamic processes at the *** biomolecular nanodynamics is therefore key to obtaining a mechanistic understanding of the energies and molecular driving forces that controlbiomolecular ***-molecule fluorescence resonance energy transfer(smFRET)is a powerful technique to observe inreal-time how a single biomolecule proceeds through its functional cycle involving a sequence of distinct structural ***,this technique is fundamentally limited by irreversible photobleaching,causing the untimely end of the experiment andthus,a narrow temporal bandwidth of≤3 orders of ***,we introduce“DyeCycling”,a measurement scheme withwhich we aim to break the photobleaching limit in *** introduce the concept of spontaneous dye replacement bysimulations,and as an experimental proof-of-concept,we demonstrate the intermittent observation of a single biomolecule forone hour with a time resolution of ***,DyeCycling can provide>100-fold more information per singlemolecule than conventional *** discuss the experimental implementation of DyeCycling,its current and fundamentallimitations,and specific biological use *** its general simplicity and versatility,DyeCycling has the potential torevolutionize the field of time-resolved smFRET,where it may serve to unravel a wealth of biomolecular dynamics by bridgingfrom milliseconds to the hour range.

关键词： biomolecular dynamics single-molecule fluorescence resonance energy transfer(smFRET) photobleaching conformational changes single-molecule kinetics

Wahi, a discrete global grid gazetteer built using linked open data

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International Journal of Digital Earth 2017年第5期10卷 490-503页

作者： benjamin Adams Department of Computer Science Centre for eResearchThe University of AucklandAucklandNew Zealand

Discrete global grid systems have become an important component of Digital Earth ***,previously there has not existed an easy way to map between named places(toponyms)and the cells of a discrete global grid *** lack of such a tool has limited the opportunities to synthesize social place-based data with the more standard Earth and environmental science data currently being analyzed in Digital Earth *** paper introduces Wāhi,the first gazetteer to map entities from the GeoNames database to multiple discrete global grid systems.A gazetteer service is presented that exposes the grid system and the associated gazetteer data as Linked Data.A set of use cases for the discrete global grid gazetteer is discussed.

关键词： Discrete global grid gazetteer linked data place toponym Digital Earth

Integrating high levels of variable renewable energy into electric power systems

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Journal of Modern Power Systems and Clean Energy 2017年第6期5卷 831-837页

作者： benjamin krOPOSKI National Renewable Energy Laboratory GoldenCO 80401USA

As more variable renewable energy(VRE)such as wind and solar are integrated into electric power systems,technical challenges arise from the need to maintain the balance between load and generation at all *** paper examines the challenges with integrating ultrahigh levels of VRE into electric power system,reviews a range of solutions to these challenges,and provides a description of several examples of ultra-high VRE systems that are in operation today.

关键词： High penetration Variable renewable energy Grid operation Wind Solar

Artificial sweetener sucralose: a possible modulator of autoimmune diseases

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Signal Transduction and Targeted Therapy 2023年第11期8卷 5123-5125页

作者： Nicolle kränkel Ursula Rauch-kroehnert Deutsches Herzzentrum der Charité Klinik für KardiologieAngiologie und IntensivmedizinCampus Benjamin-Franklin(CBF)12203BerlinGermany DZHK(german Centre for Cardiovascular Research) Partner site BerlinBerlinGermany Friede Springer—Centre of Cardiovascular Prevention@Charité Charité—University Medicine BerlinBerlinGermany

In their research article in Nature in March 2023,Fabio Zani and colleagues reported that high concentrations of the zero-calorie artificial sweetener sucralose affected the proliferation and differentiation of T cells toward interferon-γ-producing subsets,with no effect observed for B cells and myeloid cells.1 The publication has raised high hopes in the lay press on a widely available cure for patients suffering from autoimmune diseases.

关键词： autoimmune interferon diseases

Can Distributed Ledgers Help to Overcome the Need of Labeled Data for Agricultural Machine Learning Tasks?

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Plant Phenomics 2023年第3期5卷 391-394页

作者： Stefan Paulus benjamin Leiding Institute of Sugar Beet Research Holtenser Landstr.7737079 GöttingenGermany Institute for Software and Systems Engineering TU ClausthalWallstr.638640 GoslarGermany

Introduction Plant phenotyping describes the result of the interaction of genotype with the environment[1].This is performed with high throughput in greenhouses by automated screening systems using different types of imaging and non-imaging sensors[2].The high-throughput imaging routines result in large amounts of data,which require sophisticated processing *** and reusing phenotype-related data are not common,because its acquisition and processing are resource costly and technically intensive[3].

关键词： routine processing throughput

Gender disparities and woman-specific trends in Barrett’s esophagus in the United States:An 11-year nationwide populationbased study

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World Journal of Methodology 2025年第1期15卷 60-71页

作者： Karina Fatakhova Faisal Inayat Hassam Ali Pratik Patel Attiq Ur Rehman Arslan Afzal Muhammad Sarfraz Shiza Sarfraz Gul Nawaz Ahtshamullah Chaudhry Rubaid Dhillon Arthur Dilibe benjamin Glazebnik Lindsey Jones Emily Glazer Division of Gastroenterology and Hepatology Mather Hospital and Zucker School of Medicine at Hofstra UniversityPort JeffersonNY 11777United States Department of Internal Medicine Allama Iqbal Medical CollegeLahorePunjab 54550Pakistan Division of Gastroenterology and Hepatology East Carolina University Brody School of MedicineGreenvilleNC 27834United States Division of Gastroenterology and Hepatology Geisinger Wyoming Valley Medical CenterWilkes-BarrePA 18711United States Department of Internal Medicine East Carolina University Brody School of MedicineGreenvilleNC 27834United States Department of Internal Medicine St.Dominic's HospitalJacksonMS 39216United States Department of Gastroenterology Hepatologyand NutritionCleveland Clinic FoundationClevelandOH 44195United States Department of Internal Medicine Mather Hospital and Hofstra University ZuckerSchool of MedicinePort JeffersonNY 11777United States

BACKGROUND Barrett's esophagus(BE)is a known premalignant precursor to esophageal adenocarcinoma(EAC).The prevalence rates continue to rise in the United States,but many patients who are at risk of EAC are not *** practice guidelines include male gender as a predisposing factor for BE and *** population-based clinical evidence regarding female gender remains *** To study comparative trends of gender disparities in patients with BE in the United *** A nationwide retrospective study was conducted using the 2009-2019 National Inpatient Sample(NIS)*** with a primary or secondary diagnosis code of BE were *** major outcome of interest was determining the gender disparities in patients with *** analysis for respective outcomes for females was also reported to ascertain any time-based *** We identified 1204190 patients with BE for the study *** the included patients,717439(59.6%)were men and 486751(40.4%)were *** mean age was higher in women than in men(67.1±0.4 vs 66.6±0.3 years,P<0.001).The rate of BE per 100000 total NIS hospitalizations for males increased from 144.6 in 2009 to 213.4 in 2019(P<0.001).The rate for females increased from 96.8 in 2009 to 148.7 in 2019(P<0.001).There was a higher frequency of obesity among women compared to men(17.4%vs 12.6%,P<0.001).Obesity prevalence among females increased from 12.3%in 2009 to 21.9%in 2019(P<0.001).A lower prevalence of smoking was noted in women than in men(20.8%vs 35.7%,P<0.001).However,trend analysis showed an increasing prevalence of smoking among women,from 12.9%in 2009 to 30.7%in 2019(P<0.001).Additionally,there was a lower prevalence of alcohol abuse,Helicobacter pylori(***),and diabetes mellitus among females than males(P<0.001).Trend analysis showed an increasing prevalence of alcohol use disorder and a decreasing prevalence of *** and diabetes mellitus among women(P<0.001).CONCLUSION The prevalence of BE among

关键词： Barrett’s esophagus Gender disparity Epidemiological trends Esophageal adenocarcinoma Screening endoscopy Female gender Risk factors